Glaucoma is a complex and heterogeneous optic neuropathy and is a leading cause of blindness in the United States. Many pathways contribute to glaucoma pathogenesis, including, but not limited to, high intraocular pressure (IOP), optic nerve cupping, and thin central corneal thickness. Many of the molecular pathways that underlie glaucoma are incompletely defined. This is evident in the fact that the only current way of treating glaucoma is through approaches that target the IOP pathway. To make advances in developing earlier glaucoma detection mechanisms and alternative therapeutics, there is a need to more thoroughly define the underlying pathways of glaucoma. This can be accomplished through genetics by identifying the genes of traits that are quantitatively associated with glaucoma. The overall objective of this application is to identify molecular pathways that contribute to central corneal thickness (CCT), using it as an entry point for studying the etiology of glaucoma. The central hypothesis is that some of the same genetic alleles and biological pathways that cause thin CCT also cause glaucoma susceptibility. The rationale for using CCT to determine molecular pathways relevant to glaucoma is that by using a single, less complex component of glaucoma, new glaucoma susceptibility genes will be discovered. These studies will therefore implicate functional pathways in glaucoma pathogenesis, which will lay the groundwork for devising better strategies for treatment and early detection of the disease. To obtain the overall objective of this application, the central hypothesis will be tested by pursuing two specific aims: 1) Identify genes that regulate CCT in mice using quantitative genetics;and 2) Identify the extent to which Cctq1 (i.e., central corneal thickness QTL 1) influences glaucomatous phenotypes. Under the first aim, the gene on mouse chromosome 7 that regulates the magnitude of CCT will be identified using genetic mapping, bioinformatics, and DNA sequencing. Under the second aim, the already identified CCT-regulating locus (Cctq1) will be tested for its influence on cells and tissues that are impacted during glaucoma pathology using functional and physiological approaches. The proposed research is significant because the genes that influence CCT in mice are likely to be those that influence CCT in humans. This knowledge will provide insights into mechanisms that are likely to underlie glaucoma pathophysiology in humans, and that can ultimately be applied to human studies. PUBLIC HEALTH RELEVANCE: Glaucoma is a heritable ocular disease that causes blindness in millions of people worldwide. Our goal is to uncover new molecular pathways that contribute to glaucoma by identifying the genes that regulate an important risk factor, thin central corneal thickness. The research proposed in this application is relevant to NIH's mission because it will lead to the discovery of genes relevant to glaucoma, which will catalyze the unraveling of disease mechanisms, and ultimately, the ability to devise strategies for preventing and/or treating the disease.